ABSTRACT In the US, an estimated 1.2 million people are living with the Human Immunodeficiency virus (HIV). In spite of considerable progress, anti-retroviral therapy (ART) remains the only treatment option. The long-term success of ART is dependent on identification of new drugs against novel therapeutic targets due to toxicity of current drugs and emergence of ART-resistant viruses. Thus there is a critical need for continued development of compounds directed against novel viral and cellular targets. HIV-1 capsid protein (CA) has emerged as an important and legitimate therapeutic target that is currently clinically unexploited. CA is the primary structural protein of HIV and plays a critical role in both late and early stages of the viral replication cycle. While it is well established that the CA is involved in reverse transcription and nuclear entry, there is indirect evidence on the effects of CA in HIV-1 integration. This proposal will generate new knowledge on the mechanism by which CA regulates HIV-1 integration, thus facilitating antiviral drug development. The overall goal of this proposal is to understand the biochemical basis underlying the role of HIV-1 CA in viral integration. HIV enters the target cell by fusion of the viral membrane with the cellular membrane, releasing the viral core into the cytoplasm of the target cell. The HIV-1 core consists of the genomic RNA and associated viral proteins encased by the conical viral capsid. Functional studies of HIV-1 variants indicate that the proper assembly, morphology, and stability of the capsid core are all essential for HIV-1 infectivity. HIV-1 capsid (CA) is also now established to be a key determinant of the ability of HIV-1 to infect non-dividing cells. In particular, CA is genetically and functionally implicated in nuclear import of the reverse transcribed provirus, by mediating interactions with cellular transport factors. A key knowledge gap in the early stages of HIV-1 infection is the role of CA in viral integration. This proposal will span this knowledge gap through three specific aims. Aim 1: To define the effects of capsid stability on HIV-1 preintegration complex (PIC) activity and viral DNA integrity. Aim 2: To determine whether integration activity is dependent on CA levels in the PICs. Aim 3: To interrogate whether remodeling of the PICs by CA targeting host factors alter integration activity. Results from this proposal will significantly improve our understanding of CA?s role in HIV-1 integration and facilitate development of novel anti-viral therapy.